Epstein-Barr virus (EBV) is a human gamma herpesvirus that infects approximately 95% of the population and remains latent in memory B cells as a chromatin-associated multicopy episome. EBV infection is causally associated with several pathologies including infectious mononucleosis, different types of lymphomas and gastric carcinoma. This heterogeneity in EBV-associated diseases may reflect the different gene expression programs that EBV adopts in different cell types and host-cell conditions. Epigenetic modifications and alternative viral chromatin conformations contribute to the establishment and maintenance of these alternative viral gene expression programs, which are referred to as latency types. Although we know that chromatin- organizing factors, such as CTCF, affect the epigenetic state of the EBV episome we know little about the mechanisms that govern EBV genome plasticity and function and how EBV manipulates the host epigenetic machinery to avoid complete epigenetic silencing of viral latent promoters. The long-term goal of this project is to understand how EBV hijacks host epigenetic machinery to establish a latent infection, regulating both viral and host gene expression. Post-translational modifications regulate several cellular processes including the host response against pathogens. Poly-ADP-ribosylation consists of the attachment of negatively charged polymers of ADP-ribose to acceptor proteins. The reaction is catalyzed by members of the Poly(ADP-ribose) polymerase (PARP) family. In previous work, we demonstrated that PARP1 regulates EBV replication by interacting with the viral genome. Our preliminary work provides new genome wide and biochemical data that reveals for the first time that LMP1 activates PARP1 and that PARP1 activity prevents EZH2 from silencing the viral genome. Thus, we hypothesize that the EBV protein LMP1 affects viral gene expression by altering chromatin structure through PARP1/EZH2 interaction. Our project aims to fill the gap in our understanding of the epigenetic regulation of the EBV genome. To achieve our goal, we aim to: 1) how PARP1 activation regulates EBV latency programs; and 2) determine if EZH2 plays a role in regulating EBV latency. Completion of this project will reveal new mechanisms by which EBV can contribute to maintain and switch between different gene expression programs observed in infected cells. It will also identify new potential therapeutic targets for EBV infection and EBV-associated malignancies.